[Not Applicable]
This invention relates the regulation of vascular hemodynamics in various pathologies. In particular this invention pertains to the discovery that L-arginine and type V phosphodiesterases act synergistically to inhibit vasospasm and/or to induce vasodilation.
Impotence (erectile dysfunction) is the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. It has recently been estimated that approximately 10 million American men are impotent (Shabsigh et al. (1988) Urology32: 83-90; Furlow (1985) Med Aspects Hum. Sex. 19:13-16). Impotence is recognized to be an age-dependent disorder, with an incidence of 1.9 percent at 40 years of age and 25 percent at 65 years of age (Kinsey et al. (1948) pages 218-262 in Sexual Behavior in the Human Male; A. C. Kinsey et al., eds., Philadelphia, Pa.: W. B. Saunders). In 1985 in the United States, impotence accounted for more than several hundred thousand outpatient visits to physicians Rational Center for Health Statistics (National Hospital Discharge Survey, 1985, Bethesda, Md., Department of Health and Human Services, 1989 D-ES publication no. 87-1751). Depending on the nature and cause of the problem, treatments include psychosexual therapy, hormonal therapy, administration of vasodilators such as nitroglycerin and xcex1-adrenergic blocking agents (xe2x80x9cxcex1-blockers-xe2x80x9d), oral administration of other pharmaceutical agents, vascular surgery, implanted penile prostheses, vacuum constriction devices and external aids such as penile splints to support the penis or penile constricting rings to alter the flow of blood through the penis.
Recent approaches to the treatment of impotence involve the use of type V phosphodiesterase inhibitors (e.g. Viagra(trademark)) increase vasodilation. Viagra(trademark), has demonstrated significant side effects. In addition, interaction with other systemically administered medications has posed substantial risks.
Vasodilators been of interest and some use in the management of heart disease, in particular in the management of perioperative myocardial ischemia and, in certain cases, in the management of acute myocardial infarction. One of the possible etiologies of perioperative myocardial ischemia is impaired endothelium-dependent coronary flow (Hasdai (1997) Circulation, 96(10): 3390-3395). Endothelial cells contribute to the control of local vascular tone by formation of nitric oxide (NO) (Furchgott et al. (1987) Blood Vessels, 24(3): 145-149). In patients with atherosclerotic coronary arteries, basal secretion of NO is lower (Chester et al. (1990) Lancet, 336(8720): 897-900) and NO-mediated endothelium-dependent relaxations fail to occur. (Chester et al. supra.; Bossaller (1987) Basic Res Cardiol, 82(4): 396-404; Golino et al. (1991) N Engl J Med., 324(10): 641-648). As a consequence, NO-dependent factors which cause vasodilation in normal coronary arteries, paradoxically cause vasoconstriction in atherosclerotic vessels (Golino et al. supra.). Endothelial dysfunction may result in platelet adhesion, aggregation, and platelet-induced contractions of coronary smooth muscle, and thus facilitate events such a vasospasm, myocardial ischemia, and coronary thrombosis (Pearson (1991) Ann Thorac Surg, 51(5): 788-793).
In particular this invention pertains to the discovery that L-arginine and type V phosphodiesterases act synergistically to inhibit vasospasm and/or to induce vasodilation. The combination is particularly useful in the treatment of erectile dysfunction and/or various cardiac pathologies. Thus, in one embodiment, this invention provides methods for ameliorating erectile dysfunction in a male individual. The methods involve administering to the individual an effective amount of a pharmaceutical composition comprising a type V phosphodiesterase inhibitor and L-arginine. In preferred embodiments, the type V phosphodiesterase inhibitor zaprinast; dipyridamole; pyrazolopyrimidinones; griseolic acid derivatives; 2-phenylpurinones; phenylpyridone derivatives; pyrimidines; pyrimidopyrimidines; purines; quinazolines; phenylpyrimidinones; imidazoquinoxalinones or aza analogues thereof; phenylpyridones; 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)propoxy]-3(2H)pyridazinone; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8,9,9a-octahydrocyclopent[4,5]imidazo[2,1- b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl)propoxy)-3-(2H)pyridazinone; 1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; and 1-[4[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]4-piperidinecarboxylic acid, or combinations thereof. In particularly preferred embodiments, the phosphodiesterase inhibitor is zaprinast, or a pyrazolopyrimidinone, or sildenafil. The method may further involve administering to the individual a beta blocker to prevent an excessive heart rate leading to ischemia. In one embodiment, the individual is given a daily dose of phosphodiesterase inhibitor in the range of approximately 0.1 to 500 mg/day. The phosphodiesterase inhibitor is can be formulated as a unit dosage pharmaceutical formulation. In certain embodiments, this method is used to amelioriate vasculogenic impotence.
In another embodiment, this invention provides methods of inducing vasodilation or inhibiting vasospasm of a coronary artery or bypass graft. The methods involve contacting the coronary artery or bypass graft with L-arginine and a type V phosphodiesterase inhibitor, whereby L-arginine and the type V phosphodiesterase inhibitor act synergistically to induce or increase vasodilation or to inhibit vasospasm of the coronary artery or bypass graft. In one embodiment, the L-arginine is preferably administered at a concentration ranging from about 10xe2x88x925 M to about 10xe2x88x922 M and the type V phosphodiestersase inhibitor is administered at a concentration sufficient to inhibit vasospasm (in combination with the L-arginine). In certain embodiments, the phosphodiesterase inhibitor concentration ranges from about 1xc3x9710xe2x88x927 M to about 5xc3x9710xe2x88x924 M to inhibit vasospasm. In particularly preferred embodiments, the type V phosphodiesterase inhibitor is sildenafil administered at a concentration ranging from about 2xc3x9710xe2x88x927 M to about 2xc3x9710xe2x88x924 M, or zaprinast administered at a concentration ranging from about 5xc3x9710xe2x88x927 M to about 5xc3x9710xe2x88x924 M.
In another embodiment, the L-arginine is administered at a concentration ranging from about 10xe2x88x925 M to about 10xe2x88x922 M and the type V phosphodiestersase inhibitor is administered at a concentration ranging from about 10xe2x88x927 M to about 10xe2x88x924 M to induce vasodilation.
In certain embodiments, the L-arginine and the phosphodiestersase inhibitor are combined in a single formulation, and, optionally, combined with a pharmaceutically acceptable excipient. In particularly preferred embodiments, the L-arginine is formulated as L-arginine hydrochloride. Preferred type V phosphodiestersase inhibitors include zaprinast, sildenafilm, DMPPO, and 1-arylnaphthalene lignan series, in which 1-(3-bromo-4,5-dimethoxyphenyl)-5-chloro-3-[4-(2-hydroxyethyl)-1- piperazinylcarbonyl]-2-(methoxycarbonyl)naphthalene hydrochloride. The contacting can involve an intravenous injection of the L-arginine and/or the phosphodiesterase inhibitor or an oral administration of the L-arginine and/or the phosphodiesterase inhibitor.
In still another embodiment, this invention provides a pharmaceutical composition for inducing vasodilation or inhibiting vasospasm of a coronary artery or bypass graft. The composition comprises L-arginine and a type V phosphodiesterase inhibitor and, optionally, further comprises a pharmaceutically acceptable excipient. One or more type V phosphodiesterase inhibitors may be included and preferred phosphodiesterase inhibitors include, but are not limited to the type V phosphodiesterase inhibitors described herein, with particularly preferred phosphodiesterase inhibitors including sildenafil, and zaprinast. The composition may be formulated in a unit dosage form for inhibiting vasospasm of a coronary artery or bypass graft, and/or for inducing vasodilation and/or for amelioriating erectile dysfunction. In particularly preferred unit dosage formulations, L-arginine is delivered at a concentration ranging from about 10xe2x88x925 M to about 10xe2x88x922 M. Phosphodiesterase inhibitors are formulated to deliver dosages as described herein.
In still another embodiment, this invention contemplates the active ingredients after administration to an organism and thus provides, in a mammal, a coronary artery or bypass graft contacted with an exogenously supplied L-arginine and an exogenously supplied phosphodiesterase inhibitor whereby the L-arginine and the phosphodiesterase inhibitor act synergistically to induce vasodilation or reducing vasospasm of said coronary artery or bypass graft. The mammal can be a non-human test animal or a human subject. The phosphodiesterase inhibitor and/or the L-arginine are preferably present at concentrations as described herein.
This invention also provides kits for inducing vasodilation or inhibiting vasospasm of a coronary artery or bypass graft, or for amelioriating erectile dysfunction. The kits preferably comprise one or more containers containing L-arginine; and a type V phosphodiesterase inhibitor. The kits may further comprise a pharmaceutically acceptable excipient. Preferred type V phosphodiesterase inhibitors and dosages are as described herein. The kit may optionally include instructional materials teaching the synergistic combination of L-arginine and a type V phosphodiesterase inhibitor to induce vasodilation of a coronary artery or bypass graft and/or to inhibit vasospasm of a coronary artery or bypass graft and/or to amelioriate erectile dysfunction. The kit may, optionally, further comprise one or more a beta blockers.
A xe2x80x9ctype V phosphodiesterase inhibitorxe2x80x9d refers to an agent that reduces (e.g. selectively reduces) or eliminates the activity of a type V phosphodiesterase. In the context of the methods and compositions of this invention type V phosphodiesterase inhibitors include salts, esters, amides, prodrugs and other derivatives of the active agents (the PDE).
The term xe2x80x9cerectile dysfunctionxe2x80x9d is intended to include any and all types of erectile dysfunction, including: vasculogenic, neurogenic, endocrinologic and psychogenic impotence (xe2x80x9cimpotencexe2x80x9d is used here in its broadest sense to indicate an inability a periodic or consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse; see U.S. Pat. No. 5,242,391); Peyronie""s syndrome; priapism; premature ejaculation; and any other condition, disease or disorder, regardless of cause or origin, which interferes with at least one of the three phases of human sexual response, i.e., desire, excitement and orgasm (see Kaplan (1979) Disorders of Sexual Desire N.Y., Brunner Mazel Book Inc.).
The terms xe2x80x9ctreatingxe2x80x9d and xe2x80x9ctreatmentxe2x80x9d as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediaton of damage. The present method of xe2x80x9ctreatingxe2x80x9d erectile dysfunction, as the term is used herein, thus encompasses both prevention of the disorder in a predisposed individual and treatment of the disorder in a clinically symptomatic individual.
The terms xe2x80x9cbeta blockerxe2x80x9d and xe2x80x9cbeta-adrenergic receptor antagonistxe2x80x9d are uses synonymously to refer to compounds that block, at least partially, an effect of the endogenous xcex2-adrenergic receptor agonists (e.g., epinephrine and norepinephrine). Many xcex2-adrenergic antagonists can also bind to and have a regulatory effect on alpha (xcex1)-adrenergic receptors. Therefore, as used herein, xcex2-adrenergic receptor antagonists include adrenergic receptor antagonists that can bind to xcex1-, as well as xcex2-adrenergic receptors.
The terms xe2x80x9cactive agent,xe2x80x9d xe2x80x9cdrugxe2x80x9d and xe2x80x9cpharmacologically active agentxe2x80x9d are used interchangeably herein to refer to a chemical material or compound that induces a desired effect. In the preferred embodiment herein, the terms refer to a type V phosphodiesterase inhibitor, L-arginine, and, optionally, a beta blocker. Included are derivatives and analogs of those compounds or classes of compounds specifically mentioned which also induce the desired effect.
The term xe2x80x9ctransdermalxe2x80x9d delivery, applicants intend to include both transdermal (or xe2x80x9cpercutaneousxe2x80x9d) and transmucosal administration, i.e., delivery by passage of a drug through the skin or mucosal tissue and into the bloodstream.
The term xe2x80x9cbody surfacexe2x80x9d will sometimes be used herein to refer to either the skin or the mucosal tissue. xe2x80x9cTransdermalxe2x80x9d delivery is also intended to encompass delivery of a drug by passage across scrotal tissue.
The term xe2x80x9ctopical administrationxe2x80x9d is used in its conventional sense to mean delivery of a topical drug or pharmacologically active agent to the skin or mucosa. xe2x80x9cCarriersxe2x80x9d or xe2x80x9cvehiclesxe2x80x9d as used herein refer to carrier materials suitable for local drug administration. Carriers and vehicles useful herein include any such materials known in the art which is nontoxic and does not interact with other components of the composition in a deleterious manner.
By an xe2x80x9ceffectivexe2x80x9d amount of a drug or pharmacologically active agent is meant a nontoxic but sufficient amount of the drug or agent to provide the desired effect, i.e., treatment of erectile dysfunction, inhibition of vasospasm, etc.